The Experts below are selected from a list of 867 Experts worldwide ranked by ideXlab platform
William Krivit - One of the best experts on this subject based on the ideXlab platform.
-
clear cells in the atrioventricular valves of infants with severe human mucopolysaccharidosis Hurler Syndrome are activated valvular interstitial cells
Cardiovascular Pathology, 2011Co-Authors: Elizabeth A Braunlin, Jakub Tolar, William Krivit, Shannon Mackeybojack, Tiwanda Masinde, Frederick J SchoenAbstract:Abstract Background Severe mucopolysaccharidosis type I (Hurler Syndrome) is an autosomal recessive lysosomal storage disease of childhood that results in accumulation of glycosaminoglycans within cardiac valves and consequent valve dysfunction. Valve thickening in mucopolysaccharidosis type I (Hurler Syndrome) is due, in part, to the presence of glycosaminoglycan-laden cells (the so-called “clear” or “Hurler” cells) within the valve that remain largely unstudied with respect to identity, origin, and function. We hypothesized that the “clear” or “Hurler” cells within the atrioventricular valves from individuals with untreated mucopolysaccharidosis type I are activated valvular interstitial cells. Methods We performed routine and immunohistochemical staining on atrioventricular valves from two infants with untreated severe mucopolysaccharidosis type I (Hurler Syndrome) and compared them to atrioventricular valve tissue from two age-matched and gender-matched normal infants. Results Despite the marked differences in their histological appearances, mucopolysaccharidosis type I valve cells have an immunohistochemical fingerprint identical to that of normal infant valvular interstitial cells. Both mucopolysaccharidosis type I valvular interstitial cells and normal infant valvular interstitial cells have the phenotype of activated myofibroblasts, as evidenced by positive staining for vimentin, smooth muscle actin, and metalloproteinase-9. However, the number of mucopolysaccharidosis type I valvular interstitial cells is significantly increased when compared to that of normal cells (P Conclusions We conclude that “clear” or “Hurler” cells are valvular interstitial cells with the immunohistochemical phenotype of activated myofibroblasts and may be engaged, albeit ineffectively, in valve repair.
-
long term outcomes of adaptive functions for children with mucopolysaccharidosis i Hurler Syndrome treated with hematopoietic stem cell transplantation
Journal of Developmental and Behavioral Pediatrics, 2006Co-Authors: Kendra Bjoraker, William Krivit, Charles Peters, Kathleen R Delaney, Elsa ShapiroAbstract:Advances in medical treatment have prolonged the lives of children with Hurler Syndrome or mucopolysaccharidosis I requiring increased attention to the assessment of their long-term outcomes and functional abilities. Adaptive functions are critical for understanding functional outcomes after treatment and developing focused interventions. We investigated the development of various adaptive functions in children who have had hematopoietic stem cell transplant (HSCT) for Hurler Syndrome and risk factors that are associated with the development of these functions. We examined the development of 41 children who had 3 or more Vineland Adaptive Behavior Scales records assessed before and after transplant. Communication, daily living skills, socialization, and motor functions were measured. While standard scores decline over time, development of skills continue with a slower than average rate compared with peers. A cross-sectional nontransplanted comparison group showed more deficits after age 2 years than the transplanted group. In contrast to cognitive ability, age at transplant was not significantly associated with ultimate adaptive level. Baseline cognitive level before HSCT and growth of cognition after HSCT were associated with adaptive functions especially for communication and daily living skills. Socialization was predicted by cumulative medical risk factors, likely due to restricted social exposure in children with complicated transplant courses. Overall, measurement of adaptive behaviors demonstrated that HSCT allows long-term slow improvement of functional outcomes for children with Hurler Syndrome. Children with Hurler Syndrome with good cognitive levels before HSCT and continued growth of cognition after HSCT show good adaptive functions. Although cognitive and orthopedic problems as well as medical complications limit adaptive ability, identifying these problems early allow beneficial targeted interventions.
-
usefulness of bone marrow transplantation in the Hurler Syndrome
American Journal of Cardiology, 2003Co-Authors: Elizabeth A Braunlin, John J. Hopwood, Charles Peters, Nanci Stauffer, John L Bass, James M Berry, William KrivitAbstract:The Hurler Syndrome, an autosomal recessive storage disease of childhood, leads to death within the first decade of life from progressive deposition of glycosaminoglycans within the myointima of the coronary arteries and airways. Cardiac ultrasound findings of patients with this Syndrome >10 years after successful bone marrow transplantation are described.
-
allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy mld and Hurler Syndrome mps ih
Bone Marrow Transplantation, 2002Co-Authors: Omer N Koc, J Day, M Nieder, Stanton L Gerson, Hillard M Lazarus, William KrivitAbstract:Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler Syndrome (MPS-IH)
-
allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy mld and Hurler Syndrome mps ih
Bone Marrow Transplantation, 2002Co-Authors: Omer N Koc, J Day, M Nieder, Stanton L Gerson, Hillard M Lazarus, William KrivitAbstract:Patients with Hurler Syndrome (mucopolysaccharidosis type-IH) and metachromatic leukodystrophy (MLD) develop significant skeletal and neurologic defects that limit their survival. Transplantation of allogeneic hematopoietic stem cells results in partial correction of the clinical manifestations. We postulated that some of these defects may be corrected by infusion of allogeneic, multipotential, bone marrow-derived mesenchymal stem cells (MSC). Patients with Hurler Syndrome (n = 5) or MLD (n = 6) who previously underwent successful bone marrow transplantation from an HLA-identical sibling were infused with 2-10 x 10(6)/kg MSCs, isolated and expanded from a bone marrow aspirate of the original donor. There was no infusion-related toxicity. In most recipients culture-purified MSCs at 2 days, 30-60 days and 6-24 months after MSC infusion remained of host type. In two patients the bone marrow-derived MSCs contained 0.4 and 2% donor MSCs by FISH 60 days after MSC infusion. In four patients with MLD there were significant improvements in nerve conduction velocities after MSC infusion. The bone mineral density was either maintained or slightly improved in all patients. There was no clinically apparent change in patients' overall health, mental and physical development after MSC infusion. We conclude that donor allogeneic MSC infusion is safe and may be associated with reversal of disease pathophysiology in some tissues. The role of MSCs in the management of Hurler Syndrome and MLD should be further evaluated.
Paul J Orchard - One of the best experts on this subject based on the ideXlab platform.
-
outcome after cord blood transplantation using busulfan pharmacokinetics targeted myeloablative conditioning for Hurler Syndrome
Biology of Blood and Marrow Transplantation, 2021Co-Authors: Su Han Lum, Weston P. Miller, Paul J Orchard, Troy C. Lund, Jaap Jan Boelens, Robert WynnAbstract:ABSTRACT We report the outcomes of cord blood transplantation (CBT) with a busulfan (Bu) pharmacokinetics-targeted myeloablative conditioning regimen in 97 children with Hurler Syndrome (HS) performed between 2004 and 2016. The median age at CBT was 10.8 months (range, 0.23 to 63.2 months). The median duration of follow-up for surviving patients was 4.2 years (range, 1.0 to 12.8 years). Five-year overall survival (OS) and engrafted survival (ES) were 88% and 79%, respectively. OS was 95% in patients who received Bu/fludarabine (Flu)/antithymocyte globulin (ATG) conditioning, 90% in those who received Bu/cyclophosphamide (Cy)/ATG, and 74% in those who received Bu/Cy/alemtuzumab (P = .02). ES was 84% for recipients of Bu/Flu/ATG conditioning, 83% for recipients of Bu/Cy/ATG conditioning, and 65% for recipients of Bu/Cy/alemtuzumab conditioning (P = .34). Receipt of washed CB units (P = .03) and HLA matching ≤6/10 (P = .02) were associated with significantly lower ES. The 1-year cumulative incidence of graft failure was 11% (95% confidence interval, 6% to 21%). Five patients (5%) had grade III-IV acute GVHD, 5 patients had limited chronic GVHD, and 1 patient had extensive GVHD. The incidence of veno-occlusive disease was higher in patients conditioned with Bu/Cy compared with those conditioned with Bu/Flu (19% [n = 10] versus 5% [n = 2]: P = .03). Of the 11 patients with graft failure, 8 (73%) were aplastic, and 3 (27%) had autologous reconstitution. Of 11 patients with graft failure, 9 underwent a second CBT, and 8 (89%) survived. Full donor chimerism was observed in 89% patients after first CBT and in all patients after second CBT. Survival after CBT for HS has improved, but better strategies are still needed to improve graft outcomes.
-
Post-transplant laronidase augmentation for children with Hurler Syndrome: biochemical outcomes
Scientific reports, 2019Co-Authors: Troy C. Lund, Lynda E. Polgreen, Weston P. Miller, Marzia Pasquali, Jakub Tolar, Aiyin Liao, Brian W Bigger, Ryan Shanley, Nicole Sando, Paul J OrchardAbstract:Allogeneic hematopoietic cell transplantation (HCT) benefits children with Hurler Syndrome (MPS-IH). However, survivors remain burdened by substantial MPS-IH related residual disease. We studied the feasibility, safety and biochemical impact of augmentative recombinant intravenous enzyme replacement therapy (IV-ERT) post transplantation. Ten children with MPS-IH and ≥2 years from successful HCT underwent IV-ERT for 2 years' duration. Patients were monitored for anti-drug antibody (ADA) development, including inhibitory capacity and changes in urinary excretion of glycosaminoglycans (uGAG). Three patients demonstrated low-level ADA at baseline, though all children tolerated IV-ERT well. Eight patients developed ADA over the 2-year study, with 3 (38%) meeting criteria for an inhibitory ADA response. The aggregate cohort experienced a reduction in uGAG from baseline to study end, which was enhanced in children with low or no ADA response. Conversely, children with inhibitory ADA showed increase in uGAG over time. IV-ERT in previously transplanted children with MPS-IH appears safe and can reduce uGAG, although this is reversed by the presence of inhibitory ADA. These data show a biochemical change after initiation of post-HCT IV-ERT, but the occurrence of ADA and inhibitory antibodies are a concern and should be monitored in future efficacy trials. This trial was registered at www.clinicaltrials.gov , NCT01173016, 07/30/2010.
-
metabolic Syndrome and cardiovascular risk factors after hematopoietic cell transplantation in severe mucopolysaccharidosis type i Hurler Syndrome
Biology of Blood and Marrow Transplantation, 2018Co-Authors: Elizabeth A Braunlin, Paul J Orchard, Julia Steinberger, Todd E Defor, Aaron S KellyAbstract:Abstract Hematopoietic cell transplantation is a life-saving procedure, but one associated with increasing long-term cardiovascular risk requiring frequent long-term follow-up. This therapy has significantly lengthened survival in mucopolysaccharidosis type IH (Hurler Syndrome), a disease with known coronary artery involvement. Metabolic Syndrome—a constellation of central obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose—is associated with increased cardiovascular risk, and occurs when any 3 or more of these 5 components is present within a single individual. The incidence of metabolic Syndrome and its components is poorly defined after transplantation for Hurler Syndrome. Chart review of all long-term survivors of hematopoietic cell transplantation for Hurler Syndrome ≥9 years of age for factors comprising the metabolic Syndrome: obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose. Sixty-three patients were evaluated, 20 of whom had components of the metabolic Syndrome available for review. There was no significant difference in age at transplantation, sex, number of transplants, pretransplant radiation, or percent engraftment between those with and without these data. Median follow-up after transplantation for the 20 patients with data was 14.3 years. Only 1 (5%) patient of this group fulfilled the criteria for metabolic Syndrome. Fifty-three percent of the patients had 1 or more components of metabolic Syndrome: the most common was high blood pressure occurring in 40%. Metabolic Syndrome is uncommon in this cohort of long-term survivors of hematopoietic cell transplantation for Hurler Syndrome but almost half of the patients had 1 or more components of the Syndrome, with high blood pressure being the most common. Further studies are needed to develop guidelines in this diagnosis as well as other nonmalignant diseases of children.
-
long term outcomes of systemic therapies for Hurler Syndrome an international multicenter comparison
Genetics in Medicine, 2018Co-Authors: Julie B. Eisengart, Kyle D. Rudser, Weston P. Miller, Paul J Orchard, Simon Jones, Troy C. Lund, Yong Xue, Ans T Van Der Ploeg, Jean Mercer, Karl Eugen MengelAbstract:Early treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood–brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler Syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler Syndrome who received long-term ERT from a young age. Long-term survival and neurologic outcomes were compared among three groups of patients with Hurler Syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years. Survival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis. As newborn screening widens treatment opportunity for Hurler Syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT.
-
the frequency of carpal tunnel Syndrome in Hurler Syndrome after peritransplant enzyme replacement therapy a retrospective comparison
Journal of Hand Surgery (European Volume), 2017Co-Authors: Mitchell Wyffels, Weston P. Miller, Paul J Orchard, Ryan Shanley, Ann E Van HeestAbstract:Purpose Children with Hurler Syndrome (HS) develop carpal tunnel Syndrome (CTS) owing to glycosaminoglycan deposition secondary to enzyme deficiency. Advancement in the treatment of the underlying enzyme deficiency now commonly includes peritransplant intravenous enzyme replacement therapy (ERT). The primary objective of this study was to determine if the use of limited ERT in addition to hematopoietic stem cell transplantation (HCT) for the treatment of children with HS reduces the incidence of surgical intervention for CTS compared with a cohort of historical controls treated with HCT alone. The secondary objectives were to evaluate the impact of demographic and transplant-related characteristics on the incidence of CTS. Lastly, the results of surgical treatment of CTS in HS are reported. Methods Medical records for a historical group of 43 HS patients who underwent HCT alone (group 1) were compared with 31 HS patients who underwent HCT + ERT (group 2). Both groups were compared for genotype, age at transplant, sex, transplant graft source, median/ulnar nerve conduction study parameters as well as the incidence and treatment of CTS. Pre- and postoperative nerve conduction studies were compared for children treated surgically for CTS. Results The cumulative incidence of CTS at 5 years for HS children treated with HCT + ERT was 51% compared with 47% for HS children treated with HCT alone. The incidence of CTS did not depend upon graft source, age at transplant, or sex. Median nerve conduction velocity for both sensory and motor potentials demonstrated significant improvement after carpal tunnel release. Conclusions Although the administration of ERT prior to and for several months after HCT has become routine in our institution, our findings do not suggest this combined therapy is sufficient to decrease the development of CTS. Surgical intervention for median nerve compression remains the treatment of choice for CTS in HS children. Type of study/level of evidence Therapeutic IV.
Jakub Tolar - One of the best experts on this subject based on the ideXlab platform.
-
Post-transplant laronidase augmentation for children with Hurler Syndrome: biochemical outcomes
Scientific reports, 2019Co-Authors: Troy C. Lund, Lynda E. Polgreen, Weston P. Miller, Marzia Pasquali, Jakub Tolar, Aiyin Liao, Brian W Bigger, Ryan Shanley, Nicole Sando, Paul J OrchardAbstract:Allogeneic hematopoietic cell transplantation (HCT) benefits children with Hurler Syndrome (MPS-IH). However, survivors remain burdened by substantial MPS-IH related residual disease. We studied the feasibility, safety and biochemical impact of augmentative recombinant intravenous enzyme replacement therapy (IV-ERT) post transplantation. Ten children with MPS-IH and ≥2 years from successful HCT underwent IV-ERT for 2 years' duration. Patients were monitored for anti-drug antibody (ADA) development, including inhibitory capacity and changes in urinary excretion of glycosaminoglycans (uGAG). Three patients demonstrated low-level ADA at baseline, though all children tolerated IV-ERT well. Eight patients developed ADA over the 2-year study, with 3 (38%) meeting criteria for an inhibitory ADA response. The aggregate cohort experienced a reduction in uGAG from baseline to study end, which was enhanced in children with low or no ADA response. Conversely, children with inhibitory ADA showed increase in uGAG over time. IV-ERT in previously transplanted children with MPS-IH appears safe and can reduce uGAG, although this is reversed by the presence of inhibitory ADA. These data show a biochemical change after initiation of post-HCT IV-ERT, but the occurrence of ADA and inhibitory antibodies are a concern and should be monitored in future efficacy trials. This trial was registered at www.clinicaltrials.gov , NCT01173016, 07/30/2010.
-
hip dysplasia in patients with Hurler Syndrome mucopolysaccharidosis type 1h
Journal of Pediatric Orthopaedics, 2013Co-Authors: Dinesh Thawrani, Lynda E. Polgreen, Jakub Tolar, Kevin Walker, Paul J OrchardAbstract:BACKGROUND Hip dysplasia is common in patients with Hurler Syndrome (HS). However, its prevalence and optimal management is not yet clear because of the rarity of the disease and the prior short life span of these patients. Recent advances in the management of these children using allogeneic hematopoietic cell transplant (HCT) has significantly increased their life expectancy, with many surviving into adulthood. This review was conducted to describe the experience of a single center with hip dysplasia in HS after HCT. METHODS We performed a retrospective review of hip dysplasia in a consecutive series of patients with HS treated with HCT from 1985 to 2008. RESULTS At 4.5 (± 2.9) years after HCT all 51 children (102 hips) with HS showed acetabular dysplasia and proximal femur valgus deformity. Mean age at HCT was 1.6 ± 0.9 years. Forty hips (39%) underwent hip reconstructive osteotomies at mean age of 6.8 ± 3.1 years. Significant radiographic improvement was noted in all radiographic parameters at 5.4 ± 3.7 years after hip surgery (P<0.001). Acetabular index improved from 33.3 degrees (± 7.9) preoperative to 24.7 degrees (± 8) after surgery, lateral center edge angle improved from -5.3 degrees (± 10.9) to 35.2 degrees (± 17.8), migration index from 50.7% (± 15.7) to 9.6% (± 13.6), and femoral-neck-shaft angle from 150.9 degrees (± 5.8) to 130.8 degrees (± 12.4). Ten of the 40 hips underwent only proximal femoral varus derotation osteotomy and 30 underwent combined proximal femoral varus derotation osteotomy+pelvic osteotomy. CONCLUSIONS This study reports high prevalence of hip dysplasia (100%) in patients with HS. As significant radiographic improvement was achieved in those patients treated with surgical interventions we recommend annual orthopaedic evaluation of hips in patients with HS after HCT and intervention with reconstructive femoral and pelvic osteotomies for their hip dysplasia.
-
enzyme replacement is associated with better cognitive outcomes after transplant in Hurler Syndrome
The Journal of Pediatrics, 2013Co-Authors: Julie B. Eisengart, Kyle D. Rudser, Chester B Whitley, Jakub Tolar, Paul J Orchard, Teresa Kivisto, Richard S Ziegler, Elsa ShapiroAbstract:Objective To investigate whether intravenous enzyme replacement therapy (ERT) benefits cognitive function in patients with mucopolysaccharidosis type IH (Hurler Syndrome) undergoing hematopoietic cell transplantation (HCT). Study design Data were obtained for 9 children treated with HCT + ERT (ERT group) and 10 children treated with HCT only (no-ERT group) from neuropsychologic evaluations before HCT and at 1-year and 2-year post-HCT follow-up. Results At 2 years after HCT, children in the ERT group lost 9.19 fewer IQ points per year compared with children in the no-ERT group ( P = .031). Furthermore, the ERT group improved in nonverbal problem solving and processing, whereas the no-ERT group declined, resulting in a difference of 9.44 points per year between the 2 groups ( P Conclusion ERT in association with HCT enhances cognitive outcomes, providing new evidence that ERT is a valuable addition to the standard transplantation protocol. Although the mechanism responsible for this improved outcome is unknown, both direct benefits and indirect effects must be considered.
-
clear cells in the atrioventricular valves of infants with severe human mucopolysaccharidosis Hurler Syndrome are activated valvular interstitial cells
Cardiovascular Pathology, 2011Co-Authors: Elizabeth A Braunlin, Jakub Tolar, William Krivit, Shannon Mackeybojack, Tiwanda Masinde, Frederick J SchoenAbstract:Abstract Background Severe mucopolysaccharidosis type I (Hurler Syndrome) is an autosomal recessive lysosomal storage disease of childhood that results in accumulation of glycosaminoglycans within cardiac valves and consequent valve dysfunction. Valve thickening in mucopolysaccharidosis type I (Hurler Syndrome) is due, in part, to the presence of glycosaminoglycan-laden cells (the so-called “clear” or “Hurler” cells) within the valve that remain largely unstudied with respect to identity, origin, and function. We hypothesized that the “clear” or “Hurler” cells within the atrioventricular valves from individuals with untreated mucopolysaccharidosis type I are activated valvular interstitial cells. Methods We performed routine and immunohistochemical staining on atrioventricular valves from two infants with untreated severe mucopolysaccharidosis type I (Hurler Syndrome) and compared them to atrioventricular valve tissue from two age-matched and gender-matched normal infants. Results Despite the marked differences in their histological appearances, mucopolysaccharidosis type I valve cells have an immunohistochemical fingerprint identical to that of normal infant valvular interstitial cells. Both mucopolysaccharidosis type I valvular interstitial cells and normal infant valvular interstitial cells have the phenotype of activated myofibroblasts, as evidenced by positive staining for vimentin, smooth muscle actin, and metalloproteinase-9. However, the number of mucopolysaccharidosis type I valvular interstitial cells is significantly increased when compared to that of normal cells (P Conclusions We conclude that “clear” or “Hurler” cells are valvular interstitial cells with the immunohistochemical phenotype of activated myofibroblasts and may be engaged, albeit ineffectively, in valve repair.
-
Lipid Composition of Whole Brain and Cerebellum in Hurler Syndrome (MPS IH) Mice
Neurochemical Research, 2011Co-Authors: Karie A. Heinecke, Jakub Tolar, Bruce R Blazar, Brandon N. Peacock, Thomas N. SeyfriedAbstract:Hurler Syndrome (MPS IH) is caused by a mutation in the gene encoding alpha-L-iduronidase (IDUA) and leads to the accumulation of partially degraded glycosaminoglycans (GAGs). Ganglioside content is known to increase secondary to GAG accumulation. Most studies in organisms with MPS IH have focused on changes in gangliosides GM3 and GM2, without the study of other lipids. We evaluated the total lipid distribution in the whole brain and cerebellum of MPS IH ( Idua ^−/−) and control ( Idua ^+/?) mice at 6 months and at 12 months of age. The content of total sialic acid and levels of gangliosides GM3, GM2, and GD3 were greater in the whole brains of Idua ^−/− mice then in Idua ^+/? mice at 12 months of age. No other significant lipid differences were found in either whole brain or in cerebellum at either age. The accumulation of ganglioside GD3 suggests that neurodegeneration occurs in the Idua ^−/− mouse brain, but not to the extent seen in human MPS IH brain.
Charles Peters - One of the best experts on this subject based on the ideXlab platform.
-
long term outcomes of adaptive functions for children with mucopolysaccharidosis i Hurler Syndrome treated with hematopoietic stem cell transplantation
Journal of Developmental and Behavioral Pediatrics, 2006Co-Authors: Kendra Bjoraker, William Krivit, Charles Peters, Kathleen R Delaney, Elsa ShapiroAbstract:Advances in medical treatment have prolonged the lives of children with Hurler Syndrome or mucopolysaccharidosis I requiring increased attention to the assessment of their long-term outcomes and functional abilities. Adaptive functions are critical for understanding functional outcomes after treatment and developing focused interventions. We investigated the development of various adaptive functions in children who have had hematopoietic stem cell transplant (HSCT) for Hurler Syndrome and risk factors that are associated with the development of these functions. We examined the development of 41 children who had 3 or more Vineland Adaptive Behavior Scales records assessed before and after transplant. Communication, daily living skills, socialization, and motor functions were measured. While standard scores decline over time, development of skills continue with a slower than average rate compared with peers. A cross-sectional nontransplanted comparison group showed more deficits after age 2 years than the transplanted group. In contrast to cognitive ability, age at transplant was not significantly associated with ultimate adaptive level. Baseline cognitive level before HSCT and growth of cognition after HSCT were associated with adaptive functions especially for communication and daily living skills. Socialization was predicted by cumulative medical risk factors, likely due to restricted social exposure in children with complicated transplant courses. Overall, measurement of adaptive behaviors demonstrated that HSCT allows long-term slow improvement of functional outcomes for children with Hurler Syndrome. Children with Hurler Syndrome with good cognitive levels before HSCT and continued growth of cognition after HSCT show good adaptive functions. Although cognitive and orthopedic problems as well as medical complications limit adaptive ability, identifying these problems early allow beneficial targeted interventions.
-
usefulness of bone marrow transplantation in the Hurler Syndrome
American Journal of Cardiology, 2003Co-Authors: Elizabeth A Braunlin, John J. Hopwood, Charles Peters, Nanci Stauffer, John L Bass, James M Berry, William KrivitAbstract:The Hurler Syndrome, an autosomal recessive storage disease of childhood, leads to death within the first decade of life from progressive deposition of glycosaminoglycans within the myointima of the coronary arteries and airways. Cardiac ultrasound findings of patients with this Syndrome >10 years after successful bone marrow transplantation are described.
-
outcome of second hematopoietic cell transplantation in Hurler Syndrome
Bone Marrow Transplantation, 2002Co-Authors: Satkiran S Grewal, Paul J Orchard, L. A. Lockman, William Krivit, Todd E Defor, Elsa Shapiro, S Abel, Richard S Ziegler, Kathryn E Dusenbery, Charles PetersAbstract:Hurler Syndrome (HS) is an autosomal recessive, inherited metabolic storage disorder due to deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. Untreated patients develop progressive mental retardation and multisystem morbidity with a median life expectancy of 5 years. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and even improvement of intellect, with long-term survival. However, children with HS have an increased incidence of graft failure, usually with concomitant autologous marrow reconstitution. Between 1983 and 2000, 71 Hurler children underwent HCT at the University of Minnesota. Of these 71, 19 (27%) experienced graft failure. We report HCT outcomes in all 11 Hurler patients receiving a second HCT at the University of Minnesota. Median age at second HCT was 25 months (range, 16 to 45 months); median time from first HCT was 8 months (range, 4 to 18.5 months). The conditioning regimen consisted of cyclophosphamide/TBI/ATG (n = 8) or busulfan/cyclophosphamide/ATG (n = 3). The source of bone marrow was an unrelated donor in six, matched sibling in four, and mismatched related in one. Five of the 11 grafts were T cell depleted prior to infusion. Overall, 10 of 11 patients showed donor-derived engraftment, of whom three developed grade 3 to 4 acute GVHD. Five of 11 patients are surviving a median of 25 months (range, 2 months to 12 years) with an overall actuarial survival of 50% (95% CI, 27% to 93%) at 4 years. All five show sustained donor engraftment with normalization of IDU activity levels. Three of five evaluable patients demonstrated stabilization of neuropsychological function after second HCT. Currently, allogeneic donor-derived hematopoiesis provides the only chance for long-term survival and improved quality of life in Hurler patients. While graft failure in Hurler patients requires further investigation, a timely second HCT can be well-tolerated and beneficial.
-
oral busulfan pharmacokinetics and engraftment in children with Hurler Syndrome and other inherited metabolic storage diseases undergoing hematopoietic cell transplantation
Bone Marrow Transplantation, 2001Co-Authors: Pamala A Jacobson, William Krivit, Todd E Defor, J J Park, Michael J Thrall, S Abel, Charles PetersAbstract:Allogeneic hematopoietic cell transplantation (HCT) is the only treatment for selected inherited metabolic storage diseases (IMSD); a significant shortcoming is failure to achieve donor-derived engraftment. This study was undertaken to determine whether busulfan pharmacokinetics (BU PK) are altered in children with IMSD and whether BU concentrations are important in achieving engraftment. BU samples were obtained from 39 IMSD children, including 20 children with Hurler Syndrome, undergoing HCT. Patients received oral BU (40 mg/m2/dose × 8 doses), cyclophosphamide (60 mg/kg/day × 2 doses) and TBI (750 cGy in one fraction) as a preparative regimen. Median (range) oral clearance corrected for bioavailability (Cl/F in ml/min/kg), area under the curve (AUC in ng min/ml) and BU plasma concentration (Cp in ng/ml) with the fourth dose were 5.2 (2.1–11.4), 318 294 (112 893–640 995) and 950 (314–1780), respectively. Children <3 years of age had lower AUC and Cp but higher Cl/F (P ⩽ 0.03). BU Cp (P = 0.06) or marrow cell dose (P = 0.32) was not different in Hurler Syndrome compared to other IMSD. A median BU Cp of 959 and 831 ng/ml was achieved in children with full and failed early engraftment, respectively. There was no difference in early and late engraftment between children with Hurler and other IMSD. In conclusion, we found no significant association between engraftment, marrow cell dose and BU exposure when combined with CY and TBI in children with IMSD. Bone Marrow Transplantation (2001) 27, 855–861.
-
oral busulfan pharmacokinetics and engraftment in children with Hurler Syndrome and other inherited metabolic storage diseases undergoing hematopoietic cell transplantation
Bone Marrow Transplantation, 2001Co-Authors: Pamala A Jacobson, William Krivit, Todd E Defor, J J Park, Michael J Thrall, S Abel, Charles PetersAbstract:Allogeneic hematopoietic cell transplantation (HCT) is the only treatment for selected inherited metabolic storage diseases (IMSD); a significant shortcoming is failure to achieve donor-derived engraftment. This study was undertaken to determine whether busulfan pharmacokinetics (BU PK) are altered in children with IMSD and whether BU concentrations are important in achieving engraftment. BU samples were obtained from 39 IMSD children, including 20 children with Hurler Syndrome, undergoing HCT. Patients received oral BU (40 mg/m(2)/dose x 8 doses), cyclophosphamide (60 mg/kg/day x 2 doses) and TBI (750 cGy in one fraction) as a preparative regimen. Median (range) oral clearance corrected for bioavailability (Cl/F in ml/min/kg), area under the curve (AUC in ng min/ml) and BU plasma concentration (Cp in ng/ml) with the fourth dose were 5.2 (2.1-11.4), 318 294 (112 893-640 995) and 950 (314-1780), respectively. Children < 3 years of age had lower AUC and Cp but higher Cl/F (P < or = 0.03). BU Cp (P = 0.06) or marrow cell dose (P = 0.32) was not different in Hurler Syndrome compared to other IMSD. A median BU Cp of 959 and 831 ng/ml was achieved in children with full and failed early engraftment, respectively. There was no difference in early and late engraftment between children with Hurler and other IMSD. In conclusion, we found no significant association between engraftment, marrow cell dose and BU exposure when combined with CY and TBI in children with IMSD.
Weston P. Miller - One of the best experts on this subject based on the ideXlab platform.
-
outcome after cord blood transplantation using busulfan pharmacokinetics targeted myeloablative conditioning for Hurler Syndrome
Biology of Blood and Marrow Transplantation, 2021Co-Authors: Su Han Lum, Weston P. Miller, Paul J Orchard, Troy C. Lund, Jaap Jan Boelens, Robert WynnAbstract:ABSTRACT We report the outcomes of cord blood transplantation (CBT) with a busulfan (Bu) pharmacokinetics-targeted myeloablative conditioning regimen in 97 children with Hurler Syndrome (HS) performed between 2004 and 2016. The median age at CBT was 10.8 months (range, 0.23 to 63.2 months). The median duration of follow-up for surviving patients was 4.2 years (range, 1.0 to 12.8 years). Five-year overall survival (OS) and engrafted survival (ES) were 88% and 79%, respectively. OS was 95% in patients who received Bu/fludarabine (Flu)/antithymocyte globulin (ATG) conditioning, 90% in those who received Bu/cyclophosphamide (Cy)/ATG, and 74% in those who received Bu/Cy/alemtuzumab (P = .02). ES was 84% for recipients of Bu/Flu/ATG conditioning, 83% for recipients of Bu/Cy/ATG conditioning, and 65% for recipients of Bu/Cy/alemtuzumab conditioning (P = .34). Receipt of washed CB units (P = .03) and HLA matching ≤6/10 (P = .02) were associated with significantly lower ES. The 1-year cumulative incidence of graft failure was 11% (95% confidence interval, 6% to 21%). Five patients (5%) had grade III-IV acute GVHD, 5 patients had limited chronic GVHD, and 1 patient had extensive GVHD. The incidence of veno-occlusive disease was higher in patients conditioned with Bu/Cy compared with those conditioned with Bu/Flu (19% [n = 10] versus 5% [n = 2]: P = .03). Of the 11 patients with graft failure, 8 (73%) were aplastic, and 3 (27%) had autologous reconstitution. Of 11 patients with graft failure, 9 underwent a second CBT, and 8 (89%) survived. Full donor chimerism was observed in 89% patients after first CBT and in all patients after second CBT. Survival after CBT for HS has improved, but better strategies are still needed to improve graft outcomes.
-
intrathecal enzyme replacement for Hurler Syndrome biomarker association with neurocognitive outcomes
Genetics in Medicine, 2019Co-Authors: Julie B. Eisengart, Kyle D. Rudser, Lynda E. Polgreen, Elizabeth I Pierpont, Patricia I Dickson, Alexander M Kaizer, Marzia Pasquali, Kelly King, Weston P. MillerAbstract:Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler Syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change. In addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association. Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant. Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler Syndrome.
-
Post-transplant laronidase augmentation for children with Hurler Syndrome: biochemical outcomes
Scientific reports, 2019Co-Authors: Troy C. Lund, Lynda E. Polgreen, Weston P. Miller, Marzia Pasquali, Jakub Tolar, Aiyin Liao, Brian W Bigger, Ryan Shanley, Nicole Sando, Paul J OrchardAbstract:Allogeneic hematopoietic cell transplantation (HCT) benefits children with Hurler Syndrome (MPS-IH). However, survivors remain burdened by substantial MPS-IH related residual disease. We studied the feasibility, safety and biochemical impact of augmentative recombinant intravenous enzyme replacement therapy (IV-ERT) post transplantation. Ten children with MPS-IH and ≥2 years from successful HCT underwent IV-ERT for 2 years' duration. Patients were monitored for anti-drug antibody (ADA) development, including inhibitory capacity and changes in urinary excretion of glycosaminoglycans (uGAG). Three patients demonstrated low-level ADA at baseline, though all children tolerated IV-ERT well. Eight patients developed ADA over the 2-year study, with 3 (38%) meeting criteria for an inhibitory ADA response. The aggregate cohort experienced a reduction in uGAG from baseline to study end, which was enhanced in children with low or no ADA response. Conversely, children with inhibitory ADA showed increase in uGAG over time. IV-ERT in previously transplanted children with MPS-IH appears safe and can reduce uGAG, although this is reversed by the presence of inhibitory ADA. These data show a biochemical change after initiation of post-HCT IV-ERT, but the occurrence of ADA and inhibitory antibodies are a concern and should be monitored in future efficacy trials. This trial was registered at www.clinicaltrials.gov , NCT01173016, 07/30/2010.
-
Intrathecal enzyme replacement for Hurler Syndrome: biomarker association with neurocognitive outcomes
Genetics in Medicine, 2019Co-Authors: Julie B. Eisengart, Kyle D. Rudser, Kelly E. King, Lynda E. Polgreen, Steven Q. Le, Elizabeth I Pierpont, Patricia I Dickson, Alexander M Kaizer, Marzia Pasquali, Weston P. MillerAbstract:PurposeAbnormalities in cerebrospinal fluid (CSF) have been reported in Hurler Syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change.MethodsIn addition to intravenous ERT and hematopoietic cell transplantation, patients ( N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association.ResultsOver treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant.ConclusionIntrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler Syndrome.
-
long term outcomes of systemic therapies for Hurler Syndrome an international multicenter comparison
Genetics in Medicine, 2018Co-Authors: Julie B. Eisengart, Kyle D. Rudser, Weston P. Miller, Paul J Orchard, Simon Jones, Troy C. Lund, Yong Xue, Ans T Van Der Ploeg, Jean Mercer, Karl Eugen MengelAbstract:Early treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood–brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler Syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler Syndrome who received long-term ERT from a young age. Long-term survival and neurologic outcomes were compared among three groups of patients with Hurler Syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years. Survival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis. As newborn screening widens treatment opportunity for Hurler Syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT.