title: Early initiation of enzyme replacement therapy for the mucopolysaccharidoses.
abstract: The mucopolysaccharidoses (MPS), a group of rare genetic disorders caused by defects in glycosaminoglycan (GAG) catabolism, are progressive, multi-systemic diseases with a high burden of morbidity. Enzyme replacement therapy (ERT) is available for MPS I, II, and VI, and may improve walking ability, endurance, and pulmonary function as evidenced by data from pivotal trials and extension studies. Despite these demonstrable benefits, cardiac valve disease, joint disease, and skeletal disease, all of which cause significant morbidity, do not generally improve with ERT if pathological changes are already established. Airway disease improves, but usually does not normalize. These limitations can be well understood by considering the varied functions of GAG in the body. Disruption of GAG catabolism has far-reaching effects due to the triggering of secondary pathogenic cascades. It appears that many of the consequences of these secondary pathogenic events, while they may improve on treatment, cannot be fully corrected even with long-term exposure to enzyme, thereby supporting the treatment of patients with MPS before the onset of clinical disease. This review examines the data from clinical trials and other studies in human patients to explore the limits of ERT as currently used, then discusses the pathophysiology, fetal tissue studies, animal studies, and sibling reports to explore the question of how early to treat an MPS patient with a firm diagnosis. The review is followed by an expert opinion on the rationale for and the benefits of early treatment.
authors.affiliation: Division of Genetics and Metabolism, Department of Pediatrics, CB 7487, Medical School Wing E Room 117, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7487, USA. Electronic address: muenzer@med.unc.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Muenzer
mesh_terms: D002675:Child, Preschool; D002986:Clinical Trials as Topic; D004413:Dysostoses / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D056947:Enzyme Replacement Therapy; D006025:Glycosaminoglycans / Q000378:metabolism; D006351:Heart Valves / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D007066:Iduronate Sulfatase / Q000627:therapeutic use*; D007596:Joints / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D009083:Mucopolysaccharidoses / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012137:Respiratory System / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D055502:Secondary Prevention
chemical_list: D006025:Glycosaminoglycans; D011994:Recombinant Proteins; D020051:N-Acetylgalactosamine-4-Sulfatase; C508864:galsulfase; D007066:Iduronate Sulfatase; C517982:idursulfase
keywords: %FVC; 12-minute walk test; 12MWT; 6-minute walk test; 6MWT; AHI; EM; ERT; Enzyme replacement therapy; FVC; GAG; Galsulfase; HSCT; IRR; IV; Idursulfase; JROM; Laronidase; MMP9; MPS; Mucopolysaccharidosis; Pre-symptomatic; apnea/hypopnea index; electron microscopy; enzyme replacement therapy; forced vital capacity; glycosaminoglycans; hematopoietic stem cell transplantation; infusion-related reaction; intravenous; joint range of motion; matrix metalloproteinase 9; mucopolysaccharidosis/mucopolysaccharidoses; percent predicted forced vital capacity; uGAG; urinary glycosaminoglycans