title: Ultrastructural analysis of dermal fibroblasts in mucopolysaccharidosis type I: Effects of enzyme replacement therapy and hematopoietic cell transplantation.
abstract: In mucopolysaccharidosis type I (MPS I; alpha-L-iduronidase deficiency), glycosaminoglycans (GAGs) accumulate in different cell types, causing characteristic vacuolization. Hematopoietic cell transplantation (HCT) and enzyme replacement therapy (ERT) both aim to restore tissue morphology by delivering alpha-L-iduronidase to the deficient cells. The authors investigated the efficacy of both therapies on dermal fibroblast morphology in 12 patients by electron microscopy of repeated skin biopsies before and during 2 years of ERT as well as before and 6 months after HCT. Cell vacuolization was rated according to a semi-quantitative scoring system. At baseline all patients showed an increased vacuolization score as compared to controls. In addition the vacuolization score was significantly higher in patients with the severe phenotype of the disease (n = 7) compared to patients with attenuated phenotypes (n = 5) (p = .009). After initiation of ERT a significant decrease in cell vacuolization was observed (p = .012). However, the response rate varied among patients, as the vacuolization score remained high during the first year of ERT in 3 patients with the severe phenotype. In all patients who received a successful HCT (n = 3) only minimal disturbances in cell morphology were observed afterward. In conclusion, both ERT and HCT are capable of restoring, at least partially, dermal fibroblast morphology in MPS I.
authors.affiliation: Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Josanne
authors.initials: J
authors.lastname: Cox-Brinkman
authors.forename: Marius A
authors.initials: MA
authors.lastname: van den Bergh Weerman
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Johanna H
authors.initials: JH
authors.lastname: van der Lee
authors.forename: Carla E M
authors.initials: CE
authors.lastname: Hollak
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002648:Child; D003131:Combined Modality Therapy; D020405:Dermis / Q000378:metabolism / Q000648:ultrastructure*; D056947:Enzyme Replacement Therapy; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure*; D006025:Glycosaminoglycans / Q000652:urine; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008059:Mucopolysaccharidosis I / Q000473:pathology / Q000628:therapy* / Q000652:urine; D014617:Vacuoles / Q000648:ultrastructure
chemical_list: D006025:Glycosaminoglycans